Effect of aflibercept combined with triamcinolone acetonide on aqueous humor growth factor and inflammatory mediators in diabetic macular edema

AIM:To investigate the efficacy of aflibercept combined with sub-tenon injection of triamcinolone acetonide(TA)in treating diabetic macular edema(DME)and to examine changes in growth factors and inflammatory mediator levels in aqueous humor after injection.METHODS:Totally 67 DME patients(67 eyes)and 30 cataract patients(32 eyes)were enrolled as the DME group and the control group,respectively.The DME group was divided into the aflibercept group(34 cases)and the aflibercept combined with TA group(combined group,33 cases).The aqueous humor of both groups was collected during the study period.The aqueous levels of vascular endothelial growth factor(VEGF),monocyte chemoattractant protein-1(MCP-1),interleukin-6(IL-6),interleukin-8(IL-8),and interleukin-1β(IL-1β)were detected using a microsphere suspension array technology(Luminex 200TM).Aqueous cytokines,best-corrected visual acuity(BCVA),central macular thickness(CMT),and complications before and after treatment were compared between the aflibercept group and combined group.RESULTS:The concentrations of VEGF,MCP-1,IL-6,and IL-8 in the aqueous humor were significantly higher in the DME group than those of the control group(all P<0.01).After 1mo of surgery,the concentrations of VEGF,MCP-1,IL-6,and IL-8 in the aqueous humor were significantly lower in the combined group than those of the aflibercept group(all P<0.01).The BCVA and CMT values of the two groups were statistically different after 1 and 2mo of treatment(P<0.01).However,the difference was not statistically significant after 3mo of treatment(P>0.05).CONCLUSION:The cytokines VEGF,MCP-1,IL-6,and IL-8 in the aqueous humor of DME patients are significantly increased.Aflibercept and aflibercept combined with TA have good efficacy in DME patients,can effectively reduce CMT,improve the patient’s vision,and have high safety.Aflibercept combined with TA can quickly downregulate the aqueous humor cytokines and help to relieve macular edema rapidly.However,the long-term efficacy is comparable to that of aflibercept alone.

Intravitreal injection of conbercept for diabetic macular edema complicated with diabetic nephropathy

AIM:To observe the therapeutic effect of conbercept on diabetic macular edema(DME)complicated with diabetic nephropathy(DN).METHODS:In this retrospective study,54 patients(54 eyes)that diagnosed as DME from January 2017 to October 2021 were collected.The patients were divided into two groups:DME patients with DN(25 eyes),and DME patients without DN(29 eyes).General conditions were collected before treatment,laboratory tests include fasting blood glucose,HbA1c,microalbumin/creatinine,serum creatinine.Optical coherence tomography(OCT)was used to check the ellipsoidal zone(EZ)and external limiting membrane(ELM)integrity.Central macular thickness(CMT),best corrected visual acuity(BCVA),and retinal hyperreflective foci(HF)as well as numbers of injections were recorded.RESULTS:There were significant differences between fasting blood glucose,HbA1c,serum creatinine,urinary microalbumin/creatinine,and estimated glomerular filtration rate(eGFR)between the two groups(all P<0.05).EZ and ELM continuity in the DME+DN group was worse than that in the DME group(P<0.05).BCVA(logMAR)in the DME group was significantly better than that in the DME+DN group at the same time points during treatment(all P<0.05).CMT and HF values were significantly higher in the DME+DN group than that in the DME group at the all time points(all P<0.05)and significantly decreased in both groups with time during treatment.At 6mo after treatment,the mean number of injections in the DME+DN and DME group was 4.84±0.94 and 3.79±0.86,respectively.CONCLUSION:Conbercept has a significant effect in short-term treatment of DME patients with or without DN,and can significantly ameliorate BCVA,CMT and the number of HF,treatment efficacy of DME patients without DN is better than that of DME patients with DN.

Impact of COVID-19-related lifestyle changes on diabetic macular edema

AIM:To assess diabetic macular edema(DME)progression during the early phases of the COVID-19 pandemic,when severe societal restrictions raised the concern of possible deterioration of health in patients with systemic conditions,particularly those requiring frequent office visits.METHODS:This is a multicenter retrospective chart review of 370 patients(724 eyes)with an established diagnosis of DME seen on 3 separate visits between January 2019 and July 2021.Period 1 was January 2019 to February 2020(considered pre-COVID-19),period 2 was March 2020 to December 2020(considered the height of the pandemic;highest level of pandemic-related clinical and societal regulations)and period 3 was January 2021 to July 2021(re-adjustment to the new“pandemic norms”).Main outcome measures included visual acuity,body mass index(BMI),blood pressure(BP),hemoglobin A1c(HbA1c),macular thickness,patient adherence to scheduled ophthalmology visits,and DME treatment(s)received at each visit.To facilitate measurement of macular thickness,each macula was divided into 9 Early Treatment Diabetic Retinopathy Study(ETDRS)-defined macular sectors as measured by OCT imaging.RESULTS:There was no change of BMI,systolic BP,and diastolic BP between any of the time periods.HbA1c showed a very small increase from period 1(7.6%)to period 2(7.8%,P=0.015)and decreased back to 7.6%at period 3(P=0.12).Macular thickness decreased for 100%of macular regions.The central macular thickness decreased across all 3 periods from 329.5 to 316.6μm(P=0.0045).After analysis of multiple variables including HbA1c,BMI,adherence to scheduled appointments,different clinic centers,and treatment interventions,there was no easily identifiable subgroup of patients that experienced the increase in DME.CONCLUSION:DME doesn’t worsen during the COVID-19 pandemic,instead sustaining a very small but statistically significant improvement.While identifying a mechanism behind our findings is beyond the scope of this study,potential explanations may include a delay in retinal changes beyond our study period,an unexpected increase in treatment frequency despite pandemic restrictions,and an unanticipated pandemic-related improvement in some lifestyle factors that may have had a positive impact on DME.

Dexamethasone implant in naive versus refractory patients with diabetic macular edema:a Meta-analysis

AIM:To evaluate the efficacy and safety of the intravitreal dexamethasone implant in naive and refractory patients with diabetic macular edema(DME).METHODS:PubMed,Embase,Web of Science,and Medline databases were searched.The main outcomes were best-corrected visual acuity(BCVA)and central retinal thickness(CRT).The secondary outcomes included mean number of injections,intraoperative or postoperative complications including intraocular pressure(IOP)elevation and cataract.RESULTS:Ten comparative studies involving a total of 1000 DME eyes including 402 naive eyes and 598 refractory eyes were selected.The postoperative BCVA in the naive group was significantly better than in the refractory group[mean difference(MD)-0.11,95% confidence interval(CI)-0.17 to-0.05,P=0.0003;MD 8.69,95%CI 5.08 to 12.30,P<0.00001].Additionally,the naive group got greater improvement of BCVA change as well as more gains of BCVA letters than the refractory group[MD 7.71,95%CI 2.02 to 13.40,P=0.008;odds ratio(OR)2.99,95%CI 2.05 to 4.37,P<0.00001].The subgroup analysis revealed that the naive group had significantly higher BCVA gains of≥5,≥10,and≥15 letters compared to the refractory group(P=0.002,0.0001,0.003,respectively).No significant difference was detected between the two groups in either postoperative CRT(MD-22.36,95%CI-46.39 to 1.66,P=0.07)or the overall mean number of injections(MD-0.08,95%CI-0.38 to 0.22,P=0.61).Intraoperative and postoperative complications including the elevation of IOP(OR 0.47,95%CI 0.20 to 1.13,P=0.09)and cataract(OR 1.78,95%CI 0.97 to 3.24,P=0.06)showed no significant differences between the two groups during the follow-up time.CONCLUSION:Intravitreal dexamethasone implants for DME can improve anatomical and functional outcomes in both naive and refractory eyes and have a well-acceptable safety profile.Moreover,naive eyes maintain better visual outcomes than refractory eyes.It provides further evidence of better visual response when used for naive eyes as firstline therapy.

Effectiveness of intravitreal ranibizumab for diabetic macular edema in vitrectomized versus non-vitrectomized eyes:a Meta-analysis

AIM:To evaluate the effectiveness and safety of intravitreal ranibizumab(IVR)for diabetic macular edema(DME)in vitrectomized versus non-vitrectomized eyes.METHODS:The PubMed,EMBASE,Web of Science,Cochrane,EBSCO were comprehensively searched for studies comparing vitrectomized and non-vitrectomized eyes with DME.Clinical outcomes of best-corrected visual acuity(BCVA),central macular thickness(CMT),the mean number of intravitreal injection and adverse events were extracted and analyzed.RESULTS:Six studies involving 641 eyes were included.Final visual gain significantly improved and CMT significantly reduced in vitrectomized eyes at 6mo and 12mo visits(P<0.05).Although the mean reduction in CMT among non-vitrectomized eyes was significantly greater than in vitrectomized eyes at the 6mo[mean difference(MD)=53.57,95%confidence interval(CI):28.03 to 78.72,P<0.0001]and 12mo(MD=49.65,95%CI:19.58 to 79.72,P=0.01),no significant difference was detected in improvement in BCVA at either 6mo(MD=0.05,95%CI:-0.02 to 0.13,P=0.14)or 12mo(MD=0.03,95%CI:-0.04 to 0.09,P=0.43).Injection number of ranibizumab in non-vitrectomized eyes was significantly less than that in vitrectomized eyes during 6-month period(MD=0.60,95%CI:0.16 to 1.04,P=0.008),while there was no statistically significant difference between the two groups during 12mo of follow-up.CONCLUSION:Evidence from current study suggests that IVR was useful for both vitrectomized group and nonvitrectomized group with DME.Although less reduction in macular thickness is found in vitrectomized group,visual improvement between two groups is similar.

Dexamethasone implant for refractory macular edema secondary to diabetic retinopathy and retinal vein occlusion

AIM:To evaluate the efficacy,timing of retreatment and safety of dexamethasone(DEX)implant on macular edema(ME)secondary to diabetic retinopathy(DME)and retinal vein occlusion(RVO-ME)patients who were refractory to anti-vascular endothelial growth factor(VEGF)treatment.METHODS:This retrospective study included 37 eyes received at least one DEX implant treatment for DME or RVO-ME between January 1,2019,and January 1,2023.These refractory DME and RVO-ME cases received at least 5 anti-VEGF injections and failure to gain more than 5 letters or a significant reduction in central retinal thickness(CRT).The best corrected visual acuity(BCVA)and CRT were measured at baseline,and at 1,3,4 and 6mo post-DEX implant injection.Adverse events such as elevated intraocular pressure(IOP)and cataract were recorded.RESULTS:For RVO cases(n=22),there was a significant increase in BCVA from 0.27±0.19 to 0.35±0.20 at 6mo post-DEX injection(P<0.05)and CRT decreased from 472.1±90.6 to 240.5±39.0μm at 6mo(P<0.0001).DME cases(n=15)experienced an improvement in BCVA from 0.26±0.15 to 0.43±0.20 at 6mo post-DEX implant injection(P=0.0098),with CRT reducing from 445.7±55.7 to 271.7±34.1μm at 6mo(P<0.0001).Elevated IOP occurred in 45.9% of patients but was well-controlled with topical medications.No cases of cataract or other adverse events were reported.CONCLUSION:DEX implants effectively improve BCVA and reduce CRT in refractory DME and RVO-ME.Further research with larger cohorts and longer follow-up periods is needed to confirm these findings and assess long-term outcomes.

Anti-vascular endothelial growth factor drugs combined with laser photocoagulation maintain retinal ganglion cell integrity in patients with diabetic macular edema: study protocol for a prospective, non-randomized, controlled clinical trial

The integrity of retinal ganglion cells is tightly associated with diabetic macular degeneration that leads to damage and death of retinal ganglion cells,affecting vision.The major clinical treatments for diabetic macular edema are anti-vascular endothelial growth factor drugs and laser photocoagulation.However,although the macular thickness can be normalized with each of these two therapies used alone,the vision does not improve in many patients.This might result from the incomplete recovery of retinal ganglion cell injury.Therefore,a prospective,non-randomized,controlled clinical trial was designed to investigate the effect of anti-vascular endothelial growth factor drugs combined with laser photocoagulation on the integrity of retinal ganglion cells in patients with diabetic macular edema and its relationship with vision recovery.In this trial,150 patients with diabetic macular edema will be equally divided into three groups according to therapeutic methods,followed by treatment with anti-vascular endothelial growth factor drugs,laser photocoagulation therapy,and their combination.All patients will be followed up for 12 months.The primary outcome measure is retinal ganglion cell-inner plexiform layer thickness at 12 months after treatment.The secondary outcome measures include retinal ganglion cell-inner plexiform layer thickness before and 1,3,6,and 9 months after treatment,retinal nerve fiber layer thickness,best-corrected visual acuity,macular area thickness,and choroidal thickness before and 1,3,6,9,and 12 months after treatment.Safety measure is the incidence of adverse events at 1,3,6,9,and 12 months after treatment.The study protocol hopes to validate the better efficacy and safety of the combined treatment in patients with diabetic macula compared with the other two monotherapies alone during the 12-month follow-up period.The trial is designed to focus on clarifying the time-effect relationship between imaging measures related to the integrity of retinal ganglion cells and best-corrected visual acuity.The trial protocol was approved by the Medical Ethics Committee of the Affiliated Hospital of Beihua University with approval No.(2023)(26)on April 25,2023,and was registered with the Chinese Clinical Trial Registry(registration number:ChiCTR2300072478,June 14,2023,protocol version:2.0).

Aflibercept combined with triamcinolone acetonide in the treatment of diabetic macular edema:optical coherence tomography and optical coherence tomography angiography

AIM:To analyze the relationship between optical coherence tomography(OCT)and OCT angiography(OCTA)imaging in patients with diabetic macular edema(DME)who are treated with a combination of aflibercept and triamcinolone acetonide(TA).METHODS:A total of 76 eyes newly diagnosed DME were included in this study.They were randomly assigned to receive either aflibercept or a combination of aflibercept and TA.Injections once a month for a total of three injections.Central macular thickness(CMT),number of hyperreflective foci(HRF),height of subretinal fluid(SRF),and area of foveal avascular zone(FAZ)were evaluated using OCT and OCTA at baseline and after each monthly treatment.RESULTS:Both groups showed improvement in best corrected visual acuity(BCVA)and reduction in macular edema after treatment,and the difference in BCVA between the two groups was statistically significant after each treatment(P<0.05).The difference in CMT between the two groups was statistically significant after the first two injections(P<0.01),but not after the third injection(P=0.875).The number of HRF(1mo:7.41±8.25 vs 10.86±7.22,P=0.027;2mo:5.33±6.13 vs 9.12±8.61,P=0.034;3mo:3.58±3.00 vs 6.37±5.97,P=0.007)and height of SRF(1mo:82.39±39.12 vs 105.77±42.26μm,P=0.011;2mo:36.84±10.02 vs 83.59±37.78μm,P<0.01;3mo:11.57±3.29 vs 45.43±12.60μm,P<0.01)in combined group were statistically significant less than aflibercept group after each injection,while the area of FAZ showed no significant change before and after treatment in both groups.CONCLUSION:The combination therapy of aflibercept and TA shows more significant effects on DME eyes with decreased HRF and SRF.However,both aflibercept and combination therapy show no significant change in the area of FAZ.

Effects of vitrectomy combined with internal limiting membrane peeling in patients with diabetic macular edema

BACKGROUND Diabetic macular edema(DME),a chronic microvascular complication of diabetes,is a leading cause of visual impairment and blindness.Pars plana vitrectomy(PPV)can restore the normal macular structure and reduce macular edema,whereas internal limiting membrane(ILM)peeling is used to treat tractional macular diseases.Despite the advantages,there is limited research on the combined effects of PPV with ILM peeling.AIM To observe the effects of PPV combined with ILM peeling on postoperative central macular thickness(CMT),best-corrected visual acuity(BCVA),cystoid macular edema(CME)volume,and complications in patients with DME.METHODS Eighty-one patients(92 eyes)diagnosed with DME at the Beijing Shanqu Liangxiang Hospital between January and December 2022 were randomly divided to undergo PPV alone(control group:41 patients,47 eyes)or PPV+ILM peeling(stripping group:40 patients,45 eyes);a single surgeon performed all surgeries.The two groups were compared preoperatively and 1 and 3 months postoperatively.RESULTS Preoperatively,both groups had comparable values of CMT,BCVA,and CME volume(P>0.05).After surgery(both 1 and 3 months),both groups showed significant reductions in CMT,BCVA,and CME volume compared to preoperative levels,with the stripping group showing more significant reductions compared to the control group(P<0.05).Further repeated-measures ANOVA analysis for within-group differences revealed significant effects of group and time,and interaction effects for CMT,BCVA,and CME volume(P<0.05).There were no significant differences in the incidence of complications between the groups(retinal detachment:control=2,stripping=1;endophthalmitis:Control=4,stripping=1;no cases of secondary glaucoma or macular holes;χ^(2)=0.296,P=0.587).CONCLUSION PPV with ILM peeling can significantly improve the visual acuity of patients with DME,reduce CMT,and improve CME with fewer complications.

Morphological and functional changes in the macular area in diabetic macular edema after a single intravitreal injection of aflibercept

AIM:To evaluate the changes in macular morphology and function after a single intravitreal injection of aflibercept in diabetic macular edema(DME)using optical coherence tomography angiography(OCTA)and MP-3 microperimetry.METHODS:Twenty-eight patients(42 eyes)diagnosed with DME were treated with intravitreal injection of aflibercept.The changes in best corrected visual acuity(BCVA),central retinal thickness(CRT),foveal avascular zone(FAZ)area,vessel density of superficial retinal capillary plexus(SVD),vessel density of deep retinal capillary plexus(DVD),mean light sensitivity(MLS),2°fixation rate(P1),4°fixation rate(P2),and other indicators 1mo after treatment were compared;of these,BCVA was conver ted into logarithm of the minimum angle of resolution(logMAR),and the correlation among the factors was analyzed.RESULTS:After treatment,logMAR BCVA was 0.47±0.24,which was significantly better than that before treatment(0.63±0.28,P<0.001).The CRT was 359.21±107.87μm after treatment,which was significantly lower than before treatment(474.10±138.20μm,P<0.001).The FAZ area,SVD,and DVD were not significantly changed after treatment compared with the baseline.MLS was 22.16±4.20 dB after treatment,which was significantly higher than before treatment(19.63±4.23 dB,P<0.001).P2 significantly increased after treatment than before treatment(P=0.007).P1 had no significant change after treatment than before treatment(P=0.086).CONCLUSION:A single intravitreal injection of aflibercept effectively reduces macular edema and improves retinal sensitivity,fixation stability,and visual acuity,possibly without causing significant changes in the retinal vascular condition in a short time.

Guidelines from an expert panel for the management of diabetic macular edema in the Malaysian population

AIM:To derive a Malaysia guideline and consensus as part of the Malaysia Retina Group's efforts for diagnosis,treatment,and best practices of diabetic macular edema(DME).The experts'panel suggests that the treatment algorithm to be divided into groups according to involvement the central macula.The purpose of DME therapy is to improve edema and achieve the best visual results with the least amount of treatment load.METHODS:On two different occasions,a panel of 14 retinal specialists from Malaysia,together with an external expert,responded to a questionnaire on management of DME.A consensus was sought by voting after compiling,analyzing and discussion on first-phase replies on the round table discussion.A recommendation was deemed to have attained consensus when 12 out of the 14 panellists(85%)agreed with it.RESULTS:The terms target response,adequate response,nonresponse,and inadequate response were developed when the DME patients'treatment responses were first characterized.The panelists reached agreement on a number of DME treatment-related issues,including the need to classify patients prior to treatment,firstline treatment options,the right time to switch between treatment modalities,and side effects associated with steroids.From this agreement,recommendations were derived and a treatment algorithm was created.CONCLUSION:A detail and comprehensive treatment algorithm by Malaysia Retina Group for the Malaysian population provides guidance for treatment allocation of patients with DME.

Conbercept combined with laser photocoagulation in the treatment of diabetic macular edema and its influence on intraocular cytokines

BACKGROUND The prevalence of diabetes mellitus(DM)in China is high,and the base is broad.Diabetic retinopathy(DR)is a critical condition affecting the life and health of a nation and its economic development.DR is a common complication of DM.AIM To investigate the efficacy of laser photocoagulation combined with intravitreal injection of conbercept for treating macular edema.METHODS Overall,130 patients with diabetic macular edema(DME)hospitalized in The Third People’s Hospital of Changzhou from January 2019 to June 2022 were retrospectively included.According to the treatment plan,130 patients with DME were categorized into an observation and a control group,with 65 patients in each group.The control group received laser photocoagulation,and the observation group received laser photocoagulation with intravitreal injection of conbercept.Observe changes in vision,cytokines in the eye and so on.RESULTS The total efficacy rate in the observation group(93.85%)was higher than that in the control group(78.46%)(P<0.05).In both groups,the best corrected visual acuity correction effect improved after treatment,and the observation group was superior to the control group(P<0.05).Retinal thickness and central macular thickness improved after treatment,and the observation group was superior to the control group(P<0.05).The levels of vascular endothelial growth factor,interleukin-6,soluble intercellular adhesion molecule-1,and basic fibroblast growth factor in both groups improved after treatment,and the observation group was superior to the control group(P<0.05).CONCLUSION In patients with macular edema,combining laser photocoagulation and intravitreal injections of conbercept for DME is a more effective and safer strategy to improve vision,and lower intraocular cytokine levels.

Differential analysis of aqueous humor cytokine levels in patients with macular edema secondary to diabetic retinopathy or retinal vein occlusion

AIM:To evaluate the difference and the correlation between the concentrations of cytokines in the aqueous humor of eyes with macular edema secondary to diabetic retinopathy(DR)or retinal vein occlusion(RVO).METHODS:This is a retrospective case control study.The aqueous humor samples were collected during intravitreal injection of anti-vascular endothelial growth factor(VEGF)for patients diagnosed with macular edema secondary to DR(DME)or RVO(RVO-ME)at Xijing Hospital from August 2021 to July 2022.Meanwhile,aqueous humor samples during vitrectomy from patients with idiopathic macular hole(IMH)were also collected and served as controls.The aqueous humor concentrations of VEGF,platelet-derived factor(PDGF),interleukin(IL)-6,IL-8,IL-18,tumor necrosis factor-α(TNF-α)and monocyte chemoattractant protein 1(MCP-1)were measured with Human Premixed Multi-Analyte Kit(Luminex).The difference of the aqueous cytokines and the correlation between the two diseases were analyzed.RESULTS:A total of 40 eyes of 38 patients were enrolled in the study,including 13 eyes of 11 DME patients(DME group),16 eyes of 16 RVO-ME patients(RVO-ME group)and 11 eyes of 11 IMH patients(control group).The VEGF,PDGF,IL-6,IL-8,and MCP-1 levels of the aqueous humor were higher in both DME and RVO-ME groups compared with the control group(all P<0.05),the levels of TNF-αwas higher in the DME group than in the control group(P<0.05).The VEGF,IL-6,MCP-1,and TNF-αlevels in the aqueous humor were significantly higher in the DR group than those in the RVO group(all P<0.05).Correlation analyses revealed that there were complex positive correlations between IL-6,IL-8,IL-18,MCP-1,and TNF-αlevels in the aqueous humor of eyes with two diseases.CONCLUSION:Although ischemic and inflammatory factors are similarly involved in the pathogenesis of DME and RVO-ME,the roles of these factors are more significant or more likely to be activated in DR patients,suggesting different treatment strategies should be considered for the two diseases.

AB010.Promotion of BMP9/ALK1 quiescence signaling for the prevention of diabetic macular edema(DME)

Background:Sight-threatening diabetic macular edema(DME)is caused by increased microvascular permeability.While few direct vascular targeting strategies are available,VEGF pathway inhibition has shown to be effective in reducing retinal vascular leakage but is associated with non-negligible side effects.Thus,more options are needed.Vascular specific Activin-like kinase receptor type I(ALK1)pathway and its circulating ligand Bone morphogenetic protein-9(BMP9)is known for its potent quiescent and stabilizing effect on the vasculature.However,little is known about this pathway in the context of microvascular permeability associated with diabetes.We hypothesize that BMP9/ALK1 pathway is inhibited in diabetic(DB)retinas leading to vascular destabilization and leakage and that its activation could re-establish proper vascular endothelial barrier functions(EBF).Methods:The effect of hyperglycemia(i.e.,HG>10 mM of D-glucose)on Alk1 signaling was evaluated in vitro by subjecting endothelial cells(EC)to increasing concentrations of D-glucose(5,11,25 mM)and in vivo using DB mice(Streptozotocin-induced diabetes).The contribution of Alk1 signaling on EBF was evaluated using Evans Blue permeation in inducible endothelial specific Alk1 KO mice.To evaluate the potential protective effects of BMP9/Alk1 signaling on EBF,BMP9 overexpression was achieved using adenoviral delivery in DB mice.Statistical-One-Way ANOVA or Student’s t-test was used.Results:Endothelial tissue from DB mice showed a significant inhibition of BMP9/ALK1-canonical Smad1,5,8 quiescence signaling(DB n=5;CTL n=4;P<0.01),which was associated with reduced expression of target genes(JAG1,Id1,3,Hey1,2&HES).Moreover,we showed that retinal hyperpermeability associated with diabetes was exacerbated in Alk1 heterozygote mice(n=4-9/group;P<0.0001).Finally,we demonstrated that activation of Alk1 signaling in ECs prevented vascular permeability induced by HG,both in vitro(n=3;P=0.009)and in vivo(n=4-9/group;P<0.0001).Conclusions:Consistent with our hypothesis,vascular stability and quiescence induced by BMP9-ALK1 signaling is inhibited in the DB/HG endothelium which could be an important factor in vascular leakage leading to DME.Our results show that activation of this pathway could offer a therapeutically interesting future option to slow down the onset of DME.

Global trends in diabetic eye disease research from 2012 to 2021

Diabetic eye disease refers to a group of eye complications that occur in diabetic patients and include diabetic retinopathy, diabetic macular edema, diabetic cataracts, and diabetic glaucoma. However, the global epidemiology of these conditions has not been well characterized. In this study, we collected information on diabetic eye disease-related research grants from seven representative countries––the United States, China, Japan, the United Kingdom, Spain, Germany, and France––by searching for all global diabetic eye disease journal articles in the Web of Science and Pub Med databases, all global registered clinical trials in the Clinical Trials database, and new drugs approved by the United States, China, Japan, and EU agencies from 2012 to 2021. During this time period, diabetic retinopathy accounted for the vast majority(89.53%) of the 2288 government research grants that were funded to investigate diabetic eye disease, followed by diabetic macular edema(9.27%). The United States granted the most research funding for diabetic eye disease out of the seven countries assessed. The research objectives of grants focusing on diabetic retinopathy and diabetic macular edema differed by country. Additionally, the United States was dominant in terms of research output, publishing 17.53% of global papers about diabetic eye disease and receiving 22.58% of total citations. The United States and the United Kingdom led international collaborations in research into diabetic eye disease. Of the 415 clinical trials that we identified, diabetic macular edema was the major disease that was targeted for drug development(58.19%). Approximately half of the trials(49.13%) pertained to angiogenesis. However, few drugs were approved for ophthalmic(40 out of 1830;2.19%) and diabetic eye disease(3 out of 1830;0.02%) applications. Our findings show that basic and translational research related to diabetic eye disease in the past decade has not been highly active, and has yielded few new treatment methods and newly approved drugs.

Retinal vascular morphological characteristics in diabetic retinopathy: an artificial intelligence study using a transfer learning system to analyze ultra-wide field images

AIM:To investigate the morphological characteristics of retinal vessels in patients with different severity of diabetic retinopathy(DR)and in patients with or without diabetic macular edema(DME).METHODS:The 239 eyes of DR patients and 100 eyes of healthy individuals were recruited for the study.The severity of DR patients was graded as mild,moderate and severe non-proliferative diabetic retinopathy(NPDR)according to the international clinical diabetic retinopathy(ICDR)disease severity scale classification,and retinal vascular morphology was quantitatively analyzed in ultra-wide field images using RU-net and transfer learning methods.The presence of DME was determined by optical coherence tomography(OCT),and differences in vascular morphological characteristics were compared between patients with and without DME.RESULTS:Retinal vessel segmentation using RU-net and transfer learning system had an accuracy of 99%and a Dice metric of 0.76.Compared with the healthy group,the DR group had smaller vessel angles(33.68±3.01 vs 37.78±1.60),smaller fractal dimension(Df)values(1.33±0.05 vs 1.41±0.03),less vessel density(1.12±0.44 vs 2.09±0.36)and fewer vascular branches(206.1±88.8 vs 396.5±91.3),all P<0.001.As the severity of DR increased,Df values decreased,P=0.031.No significant difference between the DME and non-DME groups were observed in vascular morphological characteristics.CONCLUSION:In this study,an artificial intelligence retinal vessel segmentation system is used with 99%accuracy,thus providing with relatively satisfactory performance in the evaluation of quantitative vascular morphology.DR patients have a tendency of vascular occlusion and dropout.The presence of DME does not compromise the integral retinal vascular pattern.

Diabetic retinopathy:A review on its pathophysiology and novel treatment modalities

Diabetes mellitus(DM)is a chronic metabolic non-communicable disease with the ability to cause serious microvascular and macrovascular complications throughout the body,including in the eye.Diabetic retinopathy(DR),present in onethird of patients with diabetes,is a vision-threatening complication caused by uncontrolled diabetes,which greatly affects the retinal blood vessels and the lightsensitive inner retina,eventually leading to blindness.Several epidemiological studies elucidate that DR can vary by age of onset,duration,types of diabetes,and ethnicity.Recent studies show that the pathogenesis of diabetic retinopathy has spread its roots beyond merely being the result of hyperglycemia.The complexity of its etiopathology and diagnosis makes therapeutic intervention challenging.This review throws light on the pathological processes behind DR,the cascade of events that follow it,as well as the available and emerging treatment options.

Intravitreal therapy for the management of diabetic retinopathy:A concise review

Diabetic retinopathy(DR)is a serious microvascular complication of diabetes mellitus and may result in irreversible visual loss.Laser treatment has been the gold standard treatment for diabetic macular edema and proliferative diabetic retinopathy for many years.Of late,intravitreal therapy has emerged as a cornerstone in the management of DR.Among the diverse pharmacotherapeutic options,anti-vascular endothelial growth factor agents have demonstrated remarkable efficacy by attenuating neovascularization and reducing macular edema,thus preserving visual acuity in DR patients.

Bevacizumab for the management of diabetic macular edema

Diabetic retinopathy (DR) is a leading cause of vision loss in the working-age population and is relatedto 1%-5% of cases of blindness worldwide. Diabetic macular edema (DME) is the most frequent cause of DR vision loss and is an important public health problem. Recent studies have implicated vascular endothelial growth factor (VEGF) in DR and DME pathogenesis, as well as provided evidence of the benefits of anti-VEGF agents for the management of such conditions. Despite the benefits of intravitreal ranibizumab injection for the management of DME, the cost-effectiveness of intravitreal bevacizumab therapy has gained increasing interest in the scientific community. This review summarizes the studies examining bevacizumab for the management of DME, focusing on the efficacy and duration of the clinical benefits of decreasing DME and the improvement of best-corrected visual acuity (BCVA). There is strong evidence that intravitreal bevacizumab injection therapy has a good cost-effective profile in the management of DME and may be associated with laser photocoagulation; however, its clinical superiority in terms of the duration of DME regression and the improvement of BCVA compared with intravitreal ranibizumab and other intravitreal anti-VEGF therapies remains unclear and deserves further investigation.

Managing diabetic macular edema: The leading cause of diabetes blindness

Diabetic macular edema (DME) is the leading cause of blindness in young adults in developed countries, affecting 12% of type 1 and 28% of type 2 diabetic patients. The gold standard DME treatment should be based on a good control of glycemia along with control of lipids and renal function. However, despite the systemic metabolic control values being essential for patients with diabetic retinopathy (DR), it has proven to be insufficient for DME if it appears. With these patients, additional measures are needed in order to avoid the subsequent loss of vision. While laser treatment of DME has been the only valid treatment so far, it has been inadequate in chronic cases. The introduction of new treatments, such as intravitreal corticosteroids or anti-VEGF drugs, have recently shown their safety and efficacy and together with laser photocoagulation are becoming the treatments of choice in the management of DME.